TCR domains in T cell differentiation and (patho)physiological and therapeutic responses
Research summary:
T lymphocytes recognize pathogen-derived antigenic peptides presented by molecules from the Major Histocompatibility Complex (pMHC) via their T cell antigen receptor (TCR). This recognition event activates the T lymphocytes, which will lead to the unfolding of the adaptive immune response. Despite a relatively low affinity of the TCR for its antigen, T lymphocytes are remarkably sensitive and specific, being able to distinguish and become activated by only a few antigenic pMHCs complexes amidst a sea of irrelevant pMHC complexes. We are interested in understanding how organization of the TCR at the cell surface and identity and topology of its signaling domains affects its function. We use gene-targeted mouse models and cell lines to study the role of these domains on T cell differentiation, activation and susceptibility to autoimmune diseases. Furthermore we have developed, within the context of the H2020-MSCA-ITN EN-ACTI2NG network, a research line in which we explore structural and signaling domain variants of Chimeric Antigen Receptors in order to optimize antitumor responses.
Oligomeric TCR complexes at the cell surface of a resting human T cell. Human T cells were fixed and labeled in solution with a monoclonal antibody specific for the TCR-associated CD3 complex and 10 nm gold-conjugated protein A, followed by cell surface replica generation via the freeze-etching technique (in collaboration with the electron microscopy facility of the CBMSO). Replicas were analyzed via TEM at 8K of magnification. Insets show 8-fold enlargements of the indicated areas of the cell. Scale bar in inset: 100 nm.
| Last name | Name | Laboratory | Ext.* | Professional category | |
|---|---|---|---|---|---|
| Balabanov | Ivaylo E. | 221 | 4600 | ibalabanov(at)cbm.csic.es | Titulado Superior Grado de Doctor |
| Horndler Gil | Lydia Begoña | 221 | 4600 | lydia.horndler(at)cbm.csic.es | Titulado Sup. Actividades Tecn. y Prof.GP1 |
| Navarro García | Sofía | 221 | 4682 | snavarro(at)cbm.csic.es | Titulado Sup. Actividades Tecn. y Prof.GP1 66% |
| Van Santen | Hisse Martien | 221 | 4682 | hvansanten(at)cbm.csic.es | E.Científicos Titulares de Organismos Públicos de Investigación |
Relevant publications:
- Martínez-Riaño A, Bovolenta ER, Boccasavia VL, Ponomarenko J, Abia D, Oeste CL, Fresno M, van Santen HM*, Alarcon B*. (2019). RRAS2 shapes the TCR repertoire by setting the threshold for negative selection. J. Exp. Med. 216, 2427-2447 (*: co-corresponding authors).
- Castro M*, van Santen HM*, Ferez M, Alarcón B, Lythe GD, Molina-Paris C (2014). Receptor Pre-Clustering and T cell Responses: Insights into Molecular Mechanisms. Front. Immunol. 5, 132; doi: 10.3389/fimmu.2014.00132 (*: co-corresponding authors).
- Férez M, Castro M, Alarcon B*, van Santen HM* (2014). Cognate peptide-MHC complexes are expressed as tightly apposed nanoclusters in virus-infected cells to allow TCR crosslinking. J. Immunol. 192, 52-58 (*: co-corresponding authors).
- Fiala G, Rejas MT, Schamel WW, van Santen HM (2013). Visualization of TCR Nanoclusters via Immunogold Labeling, Freeze-Etching, and Surface Replication. Methods in Cell Biology 117, 391 - 410.
- Bains I, van Santen HM, Seddon B, Yates AW (2013). Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection. PLoS Computational Biology 9 - 7, pp. e1003102.
- Kumar R, Ferez M, Swamy M, Arechaga I, Rejas MT, Valpuesta JM, Schamel WW, Alarcon B*, van Santen HM* (2011). Increased Sensitivity of Antigen-Experienced T Cells through the Enrichment of Oligomeric T Cell Receptor Complexes. Immunity 35, 375-387 (*: co-corresponding authors).
Book chapters and reviews:
- Alarcón B, van Santen HM (2016). T Cell Receptor Triggering. In: Ralph A Bradshaw and Philip D Stahl (Editors-in-Chief), Encyclopedia of Cell Biology, Vol 3, Functional Cell Biology, pp. 650-659. Waltham, MA: Academic Press; doi:10.1016/B978-0-12-394447-4.30097-9
- Martín-Blanco N, van Santen HM, Alarcón B (2016). TCR Signaling: Proximal Signaling. In: Ratcliffe, M.J.H. (Editor in Chief), Encyclopedia of Immunobiology, Vol. 3, pp. 1–8. Oxford: Academic Press http://dx.doi.org/10.1016/B978-0-12-374279-7.11002-1
